PROJECT SUMMARY Decline in skeletal muscle function with aging is a major determinant of disability and morbidity in late life. However, the neurobiology of such decline in skeletal muscle function in normal aging is poorly understood. The proposed K08 project is a critical step towards to understanding the underlying mechanism of age-related decline of skeletal muscle function. This study uniquely focuses on the intersection between kynurenine metabolic pathway, motor neuron, neuromuscular junction (NMJ), and skeletal muscle function. Kynurenine pathway is a major route to the synthesis of Nicotinamide adenine dinucleotide (NAD), a critical coenzyme that balances redox status of all living cells. Many intermediate metabolites of kynurenine pathway are known to be potent neurotoxins, and involved in various age-related neurodegenerative diseases. The preliminary studies of this project showed alterations of kynurenine pathway in aging peripheral neuromuscular system. Herein, it is hypothesized that age-related alterations in kynurenine pathway contributes to neurodegeneration in spinal motor neurons, eventually causing age-associated muscle weakness. Aim1 propose to identify key alterations in the kynurenine pathway in the aging spinal motor neurons, using mass spectrometry, PCR, and Western blot techniques. Aim2 propose to determine the neurotoxicity of kynurenine pathway in aging neuromuscular system both in vitro and in vivo models. Finally, Aim3 tests the effects of pharmacological inhibition of a kynurenine metabolite synthesis. The findings from this study will likely identify molecular targets for age- associated muscle weakness, and used for future translational study. The proposal will take place in the Johns Hopkins School of Medicine under the mentorship of Jeremy Walston, MD, Ahmet Hoke, MD, PhD, and Robert Schwarcz, PhD. An integrated career development and mentoring plan has been also proposed to ensure Dr. Chung?s successful transition to independence. The training goals are focused on development of Dr. Chung?s expertise in kynurenine neurobiology, various molecular techniques in neuroscience research, and translational gerontology. The strength of the proposal comes from the collaboration between all of his mentors who have world-renowned expertise in aging frailty (Dr. Walston), peripheral neurodegeneration (Dr. Hoke), and kynurenine neurobiology (Dr. Schwarcz).